Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their pharmaceutical uses

ABSTRACT

The present invention relates to compounds of formula I:                    
     wherein Ar is an aryl group or a heteroaryl group; X is —NH—OH or —OH; R 1  is H, —CH(R 3 )(R 4 ), —C(O)R 3 , a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein R 3  is H or any suitable substituent and R 4  is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R 2  is CH 2 -R 5 , wherein R 5  is H or any suitable substituent, or wherein R 5  and R 4  are optionally substituted carbon atoms singly- or double-bonded to one another; and pharmaceutically acceptable prodrugs, salts, and solvates thereof. The invention further relates to methods of using these compounds, particularly as metalloproteinase inhibitors.

RELATED APPLICATION DATA

This application is a continuation of U.S. patent application Ser. No.09/073,240, filed May 6, 1998, now abandoned and claims prioritybenefits under 35 U.S.C. §119, and any other applicable treaty,statutes, or regulations, based on U.S. Provisional patent applicationSer. No. 60/045,931, filed May 9, 1997. These afore-mentionedapplications are entirely incorporated herein by reference.

Additionally, the subject matter of this application relates to theinvention of Steven L. Bender and Melwyn A. Abreo described in U.S.Provisional patent application Ser. No. 60/041,821 (filed Apr. 1, 1997)and U.S. patent application Ser. Nos. 08/825,318 (filed Apr. 1, 1997)and 09/049,949 (filed Mar. 30, 1998; attorney docket number01074.0173-01000). Each of these applications is entitled“Metalloproteinase Inhibitors, Pharmaceutical Compositions ContainingThem and Their Pharmaceutical Uses,” and each application is entirelyincorporated herein by reference.

BACKGROUND AND DESCRIPTION OF THE INVENTION

The present invention relates to compounds that inhibitmetalloproteinases, particularly matrix metalloproteinases and tumornecrosis factor-α convertase, and their pharmaceutically acceptablesalts and pharmaceutically acceptable prodrugs. The invention furtherrelates to the uses of these compounds, salts, and prodrugs for thetherapeutic treatment of humans or animals.

Matrix metalloproteinases (“MMPs”) are a family of enzymes, including,but not limited to, collagenases, gelatinases, matrilysin, andstromelysins, which are involved in the degradation and remodeling ofconnective tissues. These enzymes are found in a number of cell typesthat are found in or associated with connective tissue, such asfibroblasts, monocytes, macrophages, endothelial cells, and metastatictumor cells. They also share a number of properties, including zinc andcalcium dependence, secretion as zymogens, and 40-50% amino acidsequence homology.

Matrix metalloproteinases degrade the protein components of theextracellular matrix, i.e., the protein components found in the liningsof joints, interstitial connective tissue, basement membranes,cartilage, and the like. These proteins include collagen, proteoglycan,fibronectin, and lamanin.

Collagen is the major structural protein of mammalian tissue, comprisingone-third of the total protein in mammalian organisms, and it is anessential component of many matrix tissues, including cartilage, bone,tendons, and skin. Interstitial collagenases catalyze the initial(rate-limiting) cleavage of native collagen types I, II, III, and X.These enzymes cleave collagen into two fragments which spontaneouslydenature at physiological temperature. Denaturation of collagen involvesconversion of the rigidly coiled helix to a random coil referred to asgelatin. These gelatin (denatured collagen) fragments are then subjectto further cleavage and degradation by less specific enzymes. The netresult of collagenase cleavage is thus the loss of structural integrityin the matrix tissue (collagen collapse), an essentially irreversibleprocess.

The gelatinases include two distinct yet highly related enzymes: a72-kiloDalton (kDa) enzyme and a 92-kiloDalton enzyme. The former isreleased by fibroblasts while the latter is released by mononuclearphagocytes, neutrophils, corneal epithelial cells, tumor cells,cytotrophoblasts, and keratinocytes. Both enzymes degrade gelatins(denatured collagens), collagen types IV (basement membrane) and V,fibronectins (high molecular weight multifunctional glycoproteins foundin soft connective tissue and basement membranes), and insoluble elastin(highly cross-linked hydrophobic proteins found in load bearing fibersof mammalian connective tissue).

Stromelysins (1 and 2) cleave a broad range of matrix substrates,including lamanin, fibronectins, proteoglycans, and collagen types IVand IX (non-helical).

Matrilysin (putative metalloproteinase or PUMP) also degrades a widevariety of matrix substrates, including proteoglycans, gelatins,fibronectins, elastins, and lamanin. Matrilysin has been found inmononuclear phagocytes, rat uterine explants, and tumor cells.

In normal tissues, the activity of matrix metalloproteinases is tightlyregulated. As a result, the breakdown of connective tissue mediated bythese enzymes is generally in a dynamic equilibrium with synthesis ofnew matrix tissue.

In a number of pathological disease conditions, however, deregulation ofmatrix metalloproteinase activity leads to the uncontrolled breakdown ofextracellular matrix. These disease conditions include arthritis (e.g.,rheumatoid arthritis and osteoarthritis), periodontal disease, aberrantangiogenesis, tumor metastasis and invasion, tissue ulceration (e.g.,corneal ulceration, gastric ulceration, or epidermal ulceration), bonedisease, HIV-infection, and complications from diabetes.

Administration of matrix metalloproteinase inhibitors has been found toreduce the rate of connective tissue degradation, thereby leading to afavorable therapeutic effect. For example, in Cancer Res., vol. 53, p.2087 (1993), a synthetic matrix metalloproteinase inhibitor was shown tohave in vivo efficacy in a murine model for ovarian cancer with anapparent mode of action consistent with inhibition of matrix remodeling.The design and uses of MMP inhibitors are reviewed, for example, in J.Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29,271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp.Opin. Ther. Patents, 5, 1287-1296 (1995); and Drug Discovery Today, 1,16-26 (1996).

Matrix metalloproteinase inhibitors are also the subject of numerouspatents and patent applications, including: U.S. Pat. No. 5,189,178;U.S. Pat. No. 5,183,900; U.S. Pat. No. 5,506,242; U.S. Pat. No.5,552,419; U.S. Pat. No. 5,455,258; European Patent Application No. 0438 223; European Patent Application No. 0 276 436; WIPO InternationalPublication No. WO 92/21360; WIPO International Publication No. WO92/06966; WIPO International Publication No. WO 92/09563; WIPOInternational Publication No. WO 96/00214; WIPO InternationalPublication No. 95/35276; WIPO International Publication No. WO96/27583, WIPO International Publication No. WO 96/33172, EuropeanPatent Application No. 0 757 984, and European Patent Application No 0757 037.

Tumor necrosis factor-α (“TNF-α”) is a cytokine which is produced as a28-kDa precursor and released in an active 17-kDa form. This active formcan mediate a large number of deleterious effects in vivo, includinginflammation, fever, cardiovascular effects, haemorrhage, coagulation,and acute phase responses, similar to those seen during acute infectionsand shock states. Chronic administration of TNF-α can cause cachexia andanorexia; accumulation of excess of TNF-α can be fatal.

TNF-α convertase is a metalloproteinase involved in the biosynthesis ofTNF-α. Inhibition of TNF-α convertase inhibits production of TNF-α.

Since excessive TNF-α production has been noted in several diseaseconditions characterized by MMP-mediated tissue degradation, includingmultiple sclerosis, arthritis, and cancer, compounds which inhibit bothMMPs and TNF-α convertase are especially advantageous for the treatmentor prophylaxis of disease conditions in which both mechanisms areinvolved. Although compounds that both inhibit MMP activity and TNF-αproduction have been disclosed in WIPO International Publication Nos. WO94/24140 and WO 94/02466, there is still a need for effective MMP and/orTNF-α convertase inhibiting agents.

Because of their beneficial therapeutic effects, there is a need foreffective inhibitors of metalloproteinase activity. The presentinvention is therefore directed to certain compounds that inhibitmetalloproteinases, such as MMPs and TNF-α convertase, theirpharmaceutically acceptable prodrugs, salts, and solvates,pharmaceutical compositions containing the same, and methods of usingthe same, as well as to methods and intermediates useful in theirpreparation. Additional features and advantages of the invention will beset forth in the description which follows, and in part will be apparentfrom the description or may be learned from practice of the invention.

To achieve these and other advantages, the present invention provides acompound of formula I:

wherein Ar is an aryl group or a heteroaryl group; X is —NH—OH or —OH;R₁ is H, —CH(R₃)(R₄), —C(O)R₃, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, or a heteroaryl group, wherein R₃ is H or anysuitable substituent and R₄ is H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; R₂ isCH₂-R₅, wherein R₅ is H or any suitable substituent, or wherein R₅ andR₄ are optionally substituted carbon atoms singly- or double-bonded toone another; or a pharmaceutically acceptable prodrug, salt, or solvatethereof.

The present invention also is directed to a pharmaceutical compositioncomprising (a) a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable prodrug, salt, or solvatethereof; and (b) a pharmaceutically acceptable carrier, diluent,vehicle, or excipient.

The present invention is further directed to a method of treating amammalian disease condition mediated by metalloproteinase activity whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable prodrug, salt, or solvate thereof. The compound of formula I(or its pharmaceutically acceptable prodrug, salt, or solvate) may beadministered in the form of a pharmaceutical composition, as describedabove. Additionally, the present invention is directed to a method oftreating tumor growth, invasion, or metastasis; osteoarthritis;rheumatoid arthritis; osteoporosis; periodontitis; gingivitis; chronicdermal wounds; corneal ulceration: degenerative skin disorders; multiplesclerosis; stroke; atherosclerosis; glomerular disease; or a diseasecondition characterized by unwanted angiogenesis, such as diabeticretinopathy, macular degeneration, angiofibromas, or hemangiomas.

The present invention is still further directed to a method ofinhibiting the activity of a metalloproteinase that comprises contactingthe metalloproteinase with an effective amount of a compound of formula(I) or a pharmaceutically acceptable prodrug, salt, or solvate thereof,optionally, in the form of a pharmaceutical composition as describedabove.

As used in the present application, the following definitions apply,unless otherwise indicated:

An “alkyl group” is intended to mean a straight or branched chainmonovalent radical of saturated and/or unsaturated carbon atoms andhydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl,butynyl, propynyl, pentynyl, hexynyl, and the like, which may beunsubstituted (i.e., containing only carbon and hydrogen) or substitutedby one or more suitable substituents as defined below.

An “O-alkyl group” or “alkoxy group” is intended to mean an oxygenbonded to an alkyl group, wherein the alkyl group is as defined above.

A “cycloalkyl group” is intended to mean a non-aromatic, monovalentmonocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may besaturated or unsaturated, and which may be unsubstituted or substitutedby one or more suitable substituents as defined below, and to which maybe fused one or more heterocycloalkyl groups, aryl groups, or heteroarylgroups, which themselves may be unsubstituted or substituted by one ormore suitable substituents. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1.]heptyl, bicyclo[2.2.1.]hept-2-en-5-yl,bicyclo[2.2.2]octyl, bicyclo[3.2.1.]nonyl, bicyclo[4.3.0]nonyl,bicyclo[4.4.0]decyl, indan-1-yl, indan-2-yl, tetralin-1-yl,tetralin-2-yl, adamantyl, and the like.

A “heterocycloalkyl group” is intended to mean a non-aromatic,monovalent monocyclic, bicyclic, or tricyclic radical, which issaturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein theradical is unsubstituted or substituted by one or more suitablesubstituents as defined below, and to which may be fused one or morecycloalkyl groups, aryl groups, or heteroaryl groups, which themselvesmay be unsubstituted or substituted by one or more suitablesubstituents. Illustrative examples of heterocycloalkyl groups include,but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl,morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl,oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.

An “aryl group” is intended to mean an aromatic, monovalent monocyclic,bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ringatoms, which may be unsubstituted or substituted by one or more suitablesubstituents as defined below, and to which may be fused one or morecycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, whichthemselves may be unsubstituted or substituted by one or more suitablesubstituents. Illustrative examples of aryl groups include, but are notlimited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.

A “heteroaryl group” is intended to mean an aromatic monovalentmonocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5heteroatoms selected from nitrogen, oxygen, and sulfur, which may beunsubstituted or substituted by one or more suitable substituents asdefined below, and to which may be fused one or more cycloalkyl groups,heterocycloalkyl groups, or aryl groups, which themselves may beunsubstituted or substituted by one or more suitable substituents.Illustrative examples of heteroaryl groups include, but are not limitedto, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl,benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl,isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl,phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.

An “acyl group” is intended to mean a —C(O)—R₅— radical, wherein R₅ isany suitable substituent as defined below.

A “sulfonyl group” is intended to mean a —S(O)(O)—R₅— radical, whereinR₅ is any suitable substituent as defined below.

The term “suitable substituent” is intended to mean any of thesubstituents recognizable to those skilled in the art as not adverselyaffecting the inhibitory activity of the inventive compounds.Illustrative examples of suitable substituents include, but are notlimited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyanogroups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, arylgroups, heteroaryl groups, trialkylsilyl groups,

groups of formula (A)

wherein R_(a) is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group,

groups of formula (B)

wherein R_(a) is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group,

groups of formula (C)

wherein R_(b) and R_(c) are independently hydrogen, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group,

groups of formula (D)

wherein R_(d) is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxygroup, an alkoxy group, an amino group, an alkylamino group, adialkylamino group, or an acylamino group; and R_(e) is hydrogen, analkyl group, a cycloalkyl group, a heterocycloalkyl group, an arylgroup, a heteroaryl group, an amino group, an alkylamino group, or adialkylamino group,

groups of formula (E)

wherein R_(f) is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, or a heteroaryl group,

groups of formula (F)

wherein R_(g) and R_(h) are independently hydrogen, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group,

groups of formula (G)

wherein R_(i) is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, a heteroaryl group, or a group of formula (A),formula (B), formula (C), formula (H) (defined below), or formula (K)(defined below),

groups of formula (H)

wherein R_(j) is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxygroup, an alkoxy group, an amino group, or a group of formula (A),formula (B), formula (C) or formula (D); and wherein R_(k) is hydrogen,an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an arylgroup, a heteroaryl group, or a group of formula (A), formula (B),formula (C), formula (D), formula (E), or formula (F),

groups of formula (J)

wherein R_(l), is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or a group offormula (C), and

groups of formula (K)

wherein R_(m) and R_(n) are independently an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group, ahydroxy group, an alkoxy group, an amino group, an alkylamino group, ora dialkylamino group.

The term “suitable organic moiety” is intended to mean any organicmoiety recognizable to those skilled in the art as not adverselyaffecting the inhibitory activity of the inventive compounds.Illustrative examples of suitable organic moieties include, but are notlimited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyanogroups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, arylgroups, heteroaryl groups, trialkylsilyl groups, and

groups of formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), and (K),as defined above.

A “hydroxy group” is intended to mean the radical —OH.

An “oxo group” is intended to mean the divalent radical ═O.

A “halo group” is intended to mean any of the radicals —F, —Cl, —Br, or—I.

A “cyano group” is intended to mean the radical —C≡N.

A “nitro group” is intended to mean the radical —NO₂.

A “trialkylsilyl group” is intended to mean the radical—SiR_(p)R_(q)R_(s), where R_(p), R_(q), and R_(s) are each independentlyan alkyl group.

A “carboxy group” is intended to mean a group of formula (B) whereinR_(a) is hydrogen.

A “alkoxycarbonyl group” is intended to mean a group of formula (B)wherein R_(a) is an alkyl group as defined above.

A “carbamoyl group” is intended to mean a group of formula (C) whereinR_(b) and R_(c) are both hydrogen.

An “amino group” is intended to mean the radical —NH₂.

An “alkylamino group” is intended to mean the radical —NHR_(u), whereinR_(u) is an alkyl group as defined above.

A “dialkylamino group” is intended to mean the radical —NR_(u)R_(v),wherein R_(u) and R_(v), which are the same or different, are each analkyl group as defined above.

A “pharmaceutically acceptable prodrug” is intended to mean a compoundthat is converted under physiological conditions or by solvolysis to acompound of formula I.

A “pharmaceutically acceptable solvate” is intended to mean a solvatethat retains the biological effectiveness and properties of thebiologically active components of compounds of formula I.

Examples of pharmaceutically acceptable solvates include, but are notlimited to, compounds of formula I in combination with water,isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, orethanolamine.

In the case of solid formulations, it is understood that the inventivecompounds may exist in different forms, such as stable and metastablecrystalline forms and isotropic and amorphous forms, all of which areintended to be within the scope of the present invention.

A “pharmaceutically acceptable salt” is intended to mean those saltsthat retain the biological effectiveness and properties of the freeacids and bases and that are not biologically or otherwise undesirable.

Examples of pharmaceutically acceptable salts include, but are notlimited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired salt may be prepared byany suitable method known to the art, including treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like, or withan organic acid, such as acetic acid; maleic acid; succinic acid;mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid;glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acidand galacturonic acid; alpha-hydroxy acids such as citric acid andtartaric acid; amino acids such as aspartic acid and glutamic acid;aromatic acids such as benzoic acid and cinnamic acid; sulfonic acidssuch a p-toluenesulfonic acid or ethanesulfonic acid; or the like.

If the inventive compound is an acid, the desired salt may be preparedby any suitable method known to the art, including treatment of the freeacid with an inorganic or organic base, such as an amine (primary,secondary, or tertiary), an alkali metal hydroxide, an alkaline earthmetal hydroxide, or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids such as glycine andarginine; ammonia; primary, secondary, and tertiary amines; cyclicamines such as piperidine, morpholine, and piperazine; and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

The inventive compounds may exist as single stereoisomers, racemates,and/or mixtures of enantiomers and/or diastereomers. All such singlestereoisomers, racemates, and mixtures thereof are intended to be withinthe scope of the present invention.

As generally understood by those skilled in the art, an optically purecompound having one chiral center (i.e., one asymmetric carbon atom) isone that consists essentially of one of the two possible enantiomers(i.e., is enantiomerically pure), and an optically pure compound havingmore than one chiral center is one that is both diastereomerically pureand enantiomerically pure. Preferably, the compounds of the presentinvention are used in a form that is at least 90% optically pure, thatis, a form that contains at least 90% of a single isomer (80%enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), morepreferably at least 95% (90% e.e. or d.e.), even more preferably atleast 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98%e.e. or d.e.).

In the compounds, compositions, and methods of the present invention,preferably R₃ is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —OR₁₀, —SR₁₀,C≡C—R₁₀, —C(O)OR₁₀, C(O)NHR₁₀, wherein R₁₀ is hydrogen, an alkyl group,a cycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroarylgroup.

Preferred compounds according to the invention include compounds havingthe formula II:

wherein R₁, R₂ and X are as defined above and Z is a halogen group, analkyl group, a cycloalkyl group, a heterocycloalkyl group, an O-alkylgroup, an S-alkyl group, an aryl group, or a heteroaryl group.

Other preferred compounds include compounds of formula I where Ar is aheteroaryl group containing six ring atoms. More preferably, Ar ispyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

Other preferred compounds include those where R₅ is H and R₄ is an alkylgroup. Also preferred are those compounds where R₅ is a heteroaryl groupand those where R₅ is —CHR₆R₇, wherein R₆ is H or any suitablesubstituent and R₇ is

wherein R₈ is any suitable substituent.

In the inventive compounds, it is also preferred that R₄ is an alkylgroup and R₃ is an alkyl group, an O-alkyl group, or an S-alkyl group.More preferably, R₃ is a —CH₂CH₂— heteroaryl group, an —OCH₂— heteroarylgroup, or an —S—CH₂-heteroaryl group.

Other preferred compounds include those where R₄ and R₅ together formthe group —CH₂CH₂—.

Inventive compounds of formula I wherein X is NHOH are preferablyselected from those possessing inhibitory potencies (Ki's) against humangelatinase A (Gel A), human collagenase-3 (Coll-3), and/or humanstromelysin-1 (Strom) of less than 50 nM, and more preferably of lessthan 5 nM. Still more preferably, compounds of formula I wherein X isNHOH are selected from those possessing Ki's against Gel A and/or Coll-3of less than 0.2 nM and/or those possessing an inhibition selectivity asdefined by the ratio of Ki for human collagenase-1 (HFC) and the Ki forColl-3, of greater than 50.

Inventive compounds of formula I wherein X is OH are preferably selectedfrom those possessing Ki's against Gel A of less than 1 μM, morepreferably less than 200 nM, and still more preferably less than 50 nM.Assays for determining Ki's are described in greater detail infra.

Particularly preferred compounds falling within formula I include:

2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-Methylphenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-Phenoxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(Imidazol4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(2-(Dimethylamino)ethyl)phenoxy)benzenesulfonyl]-N-hydroxypiperidine-2-carboxamide,

2(R)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxypiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R),3(S)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-carboxamide,

2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-4-yl)methyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(imidazol-2-yl)methyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-2-yl)ethyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-4-yl)ethyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(pyrazol-3-yl)ethyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylamino)ethyl]amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-cyclohexylacetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-2-yl)ethyl]amino-N-hydroxy-2-cyclohexylacetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino-N-hydroxy-2-cyclohexylacetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-(1-acetylpiperidin-4-yl)acetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(2-(methylcarbamoyl)ethyl]amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,

2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N,3-dihydroxybutanamide,

2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methoxybutanamide,

2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-(2-methoxyethoxy)butanamide,

2(R), 3(R),3(2′(S))-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-oxopyrrolidin-2-yl)methoxy]butanamide,

2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methoxy]butanamide,

2(R)-2-(4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohexylacetamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,

2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylpiperidin-4-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[2-(dimethylamino)ethylsulfanyl]butanamide,

2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]propanamide,

2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]propanamide,

2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]propanamide,

2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N,3-dihydroxybutanamide,

2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methoxybutanamide,

2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-(2-methoxyethoxy)butanamide,

2(R), 3(R),3(2′(S))-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-oxopyrrolidin-2-yi)methoxy]butanamide,

2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methoxy]butanamide,

2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(1-methylpiperidin4-yl)acetamide,

2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohexylacetamide,

2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,

2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylpiperidin-4-yl)methylsulfanyl]butanamide,

2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[2-(dimethylamino)ethylsulfanyl]butanamide,

2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]propanamide,

2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]propanamide,

2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]propanamide,

2(R),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N,3-dihydroxybutanamide,

2(R),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methoxybutanamide,

2(R),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-(2-methoxyethoxy)butanamide,

2(R), 3(R),3(2′(S))-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-oxopyrrolidin-2-yl)methoxy]butanamide,

2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohexylacetamide,

2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclopentylacetamide,

2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclopropylacetamide,

2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,

2(S),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]butanamide,

2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-(hydroxymethyl)isoxazol-3-yl)methylsulfanyl]propanamide,

2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(phenyl)methylsulfanyl]propanamide,

2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(4-fluorophenyl)methylsulfanyl]propanamide,

2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]propanamide,

2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Methylphenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-Methoxyphenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-Phenoxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-2-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-2-[4-(4-(Imidazol4-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,and

2(R)-2-[4-(4-(2-(dimethylamino)ethyl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,

2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-Methylphenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-Phenoxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,

2(R)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(4-(2-(Dimethylamino)ethyl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,

2(R),3(S)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,and pharmaceutically acceptable prodrugs, salts, and solvates thereof.

The present invention is further directed to methods of inhibitingmetalloproteinase activity, for example in mammalian tissue, byadministering a compound of formula I, or a pharmaceutically acceptableprodrug, salt, or solvate thereof. The activity of the inventivecompounds as inhibitors of metalloproteinases, such as MMPs (includingstromelysins, collagenases, gelatinases, and/or matrilysin) and/or TNF-∝convertase, may be measured by any of the methods available to thoseskilled in the art, including in vivo and/or in vitro assays. Examplesof suitable assays for activity measurements include those described inAnal. Biochem., vol. 147, p. 437 (1985); Anal Biochem., vol. 180, p. 110(1989); FEBS, vol. 96, p. 263 (1992); and European Patent ApplicationNo. 0 606 046, the disclosures of which are incorporated herein byreference.

Administration of the compounds of formula I, or their pharmaceuticallyacceptable prodrugs, salts, or solvates, may be performed according toany of the accepted modes of administration available to those skilledin the art. Illustrative examples of suitable modes of administrationinclude oral, nasal, parenteral, topical, transdermal, and rectal.Preferably, the mode of administration is oral.

The inventive compounds of formula I, or their pharmaceuticallyacceptable prodrugs, salts, or solvates, may be administered as apharmaceutical composition in any suitable pharmaceutical formrecognizable to the skilled artisan. Suitable pharmaceutical formsinclude, but are not limited to, solid, semisolid, liquid, orlyophilized formulations, such as tablets, powders, capsules,suppositories, suspensions, and aerosols. Preferably, the pharmaceuticalform is a tablet or capsule for oral administration. The pharmaceuticalcomposition may also include suitable excipients, diluents, vehicles,and carriers, as well as other pharmaceutically active agents, dependingupon the intended use.

Acceptable methods of preparing suitable pharmaceutical forms of thepharmaceutical compositions are known to those skilled in the art. Forexample, pharmaceutical preparations may be prepared followingconventional techniques of the pharmaceutical chemist involving stepssuch as mixing, granulating, and compressing when necessary for tabletforms, or mixing, filling, and dissolving the ingredients asappropriate, to give the desired products for oral, parenteral, topical,intravaginal, intranasal, intrabronchial, intraocular, intraaural,and/or rectal administration. Illustrative examples of such methodsinclude those described in Remington's Pharmaceutical Sciences, 18thedition (1990).

Solid or liquid pharmaceutically acceptable carriers, diluents,vehicles, or excipients may be employed in the pharmaceuticalcompositions. Illustrative solid carriers include starch, lactose,calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, and stearic acid. Illustrativeliquid carriers include syrup, peanut oil, olive oil, saline solution,and water. The carrier or diluent may include a suitableprolonged-release material, such as glyceryl monostearate or glyceryldistearate, alone or with a wax. When a liquid carrier is used, thepreparation may be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid (e.g. solution), or anonaqueous or aqueous liquid suspension.

A dose of the pharmaceutical composition contains at least atherapeutically effective amount of the active compound (i.e., acompound of the formula I, or a pharmaceutically acceptable prodrug,salt, or solvate thereof), and preferably is made up of one or morepharmaceutical dosage units. An exemplary dosage unit for a mammalianhost contains an amount of from 0.1 milligram up to 500 milligrams ofactive compound per kilogram body weight of the host, preferably 0.1 to200 milligrams, more preferably 50 milligrams or less, and even morepreferably about 10 milligrams or less, per kilogram of the host weight.The selected dose may be administered to a mammal, for example, a humanpatient in need of treatment mediated by inhibition of metalloproteinaseactivity, by any known method of administrating the dose including:topically, for example, as an ointment or cream; orally; rectally, forexample, as a suppository; parenterally by injection; or continuously byintravaginal, intranasal, intrabronchial, intraaural, or intraocularinfusion.

The amount of the inventive compounds, salts, solvates, and/or prodrugsto be administered will vary based upon a number of factors, includingthe specific metalloproteinase to be inhibited, the degree of inhibitiondesired, the characteristics of the mammalian tissue in which inhibitionis desired, the metabolic stability and activity of the particularinventive compound employed, and the mode of administration. One skilledin the art may readily determine a suitable dosage according to methodsknown to the art. Preferably, the amount of inventive compound offormula I, or their pharmaceutically acceptable prodrugs, salts, orsolvates, administered ranges from 0.1 mg/kg body weight to 100 mg/kgbody weight per day.

The inventive compounds, and the salts, solvates, and prodrugs thereof,may be prepared by employing the techniques available in the art usingstarting materials that are readily available. Exemplary methods ofpreparing the inventive compounds are described below. In the followingschemes, unless otherwise indicated, R₁, R₂, and Ar are as definedabove.

As illustrated in Scheme 1, hydroxamic acids of formula Ia (compounds offormula I where X is —NH—OH) can be prepared by reacting thecorresponding carboxylic acids of formula Ib (compounds of formula Iwhere X is —OH) with hydroxylamine in the presence of a suitable peptidecoupling reagent, for example, 1,1′-carbonyldimidazole,N-(dimethylaminopropyl)-N′-ethyl carbodiimide,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate,or propanephosphonic anhydride in an inert polar solvent, such asdimethylformamide. Alternatively, compounds of formula III can bereacted with hydroxylamine in a suitable solvent mixture, such asTHF/t-butanol/dichloromethane or water/dichloromethane, preferably at 0°C., to give hydroxamic acids of formula I. Compounds of formula III aregenerally prepared, in a form directly useful for further reactionwithout isolation, by allowing carboxylic acids of formula Ib to reactwith thionyl chloride or oxalyl chloride, preferably in the presence ofa catalytic amount of dimethylformamide, in dichoromethane solvent at−78° C. to room temperature.

Alternatively, the coupling reactions described above may be carried outwith compounds of formula Ib (or III) and O-protected derivatives ofhydroxylamine (where Pg is a suitable protecting group, such as benzyl,tert-butyl, t-butyldimethylsilyl, or t-butyidiphenylsilyl) to givecompounds of formula IV. Deprotection of compounds of formula IV usingconventional methods (for example, see “Protective Groups in OrganicSynthesis”, T. W. Greene and P. G. M. Wuts, Wiley-Interscience 1991, thedisclosure of which is incorporated herein by reference) providescompounds of formula Ia.

As shown in Scheme 2, carboxylic acids of formula Ib can be prepared byreacting N-substituted-α-amino acids of formula V with arylsulfonylchlorides of formula VI, under biphasic basic conditions as described,for example, in “The Chemistry of the Amino Acids”, J. P. Greenstein andM. Winitz, Robert E. Krieger Publishing Company, 1984, p. 886-889, thedisclosure of which is incorporated herein by reference.

Alternatively, carboxylic acids Ib can be prepared by reactingN-substituted-α-amino acid derivatives VII, where Pg is any suitableprotecting group as described, for example, in “Protective Groups inOrganic Synthesis”, T. W. Greene and P. G. M. Wuts, Wiley-Interscience1991 (the disclosure of which is incorporated herein by reference), witharyl sulfonyl chlorides VI to give sulfonamides VIII under any of avariety of reaction conditions that have been reported in the literaturefor the sulfonylation of amino acid derivatives (see, for example, “TheChemistry of the Amino Acids”, J. P. Greenstein and M. Winitz, Robert E.Krieger Publishing Company, 1984, p. 886-889). Deprotection of VIII togive the acids Ib can be carried out as appropriate to the protectinggroup Pg. As is evident to those skilled in the art, manipulations offunctionality in the groups R₁, R₂, and/or Ar may be readily effected atthe stage of VII prior to the deprotection of VIII to Ib. Amino acids Vare commercially-available, or can be prepared according to methodsfamiliar to those skilled in the art.

In cases where the N-substituted α-amino acid of formula V is notreadily available, the sequence shown in Scheme 3 can be employed toprepare compounds of formula VIII. In this case, protected α-amino acidsof formula IX are sulfonylated as described above to providesulfonamides of formula X. Treatment of X with an alkylating agent R₂-Xin the presence of a suitable base, such as potassium carbonate orsodium hydride, in a aprotic solvent, such as N,N-dimethylformamide, at0° C. to 60° C., preferably at 25° C., for 1 to 24 h provides compoundsof formula VIII.

In some cases, elaboration of the R₁ group in compounds of formula X isadvantageous; one such sequence is outlined in Scheme 4, above. InScheme 4, R₁₀ is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group, and Y isoxygen or sulfur. The reaction scheme proceeds as follows. Sulfonylationof D-α-amino-β-hydroxy amino esters of formula XI (e.g., esters ofD-serine when R₄ is H, and esters of D-allo-threonine when R₄ is Me)with sulfonyl chlorides of formula VI as described above providescompounds of formula X-a. Treatment of sulfonamides of formula X-a withdiethyl azodicarboxylate and triphenylphosphine in a suitable inertsolvent, such as tetrahydrofuran, at 0° C. to 50° C. for 1 to 24 hprovides sulfonyl aziridines of formula XII. Treatment of aziridines XIIwith alcohols R₁₀—OH (i.e., where R₃ is —OR₁₀) or thiols R₁₀—SH (i.e.,where R₃ is —SR₁₀) in the presence of a suitable acid catalyst, such asboron trifluoride etherate, in an inert solvent such as dichloromethaneor 1,2-dichloroethane, for 0.5 to 48 h at 0° C. to 60° C., preferably at25° C. provides compounds of formula X-b.

Aryl sulfonyl chlorides VI are most readily available bychlorosulfonylation of the corresponding aryl phenyl ethers XIII, asoutlined in Scheme 5 above. In general, treatment of XIII with a littleover one molar equivalent of chlorosulfonic acid in a suitable inertsolvent, such as 1,2-dichloroethane or dichloromethane, at −20° C. to25° C. for a period of one to twenty-four hours generates thecorresponding sulfonic acid intermediate XIV. Without isolation, XIV canbe further converted to the sulfonyl chloride VI by reaction with achlorinating agent, such as oxalyl chloride or thionyl chloride, andoptionally cataltyic DMF. In some cases, excess chlorosulfonic acid iseffective at converting XIII directly to VI via the intermediacy of XIV.Compounds of the formula XIII are commercially-available or may bereadily prepared by those skilled in the art from commercially-availablematerials by the Ullman reaction.

Other compounds of formula I may be prepared by methods known to thoseskilled in the art in a manner analogous to the general proceduresdescribed above. Specific examples of methods used to prepare theinventive compounds are described below along with illustrativepreferred embodiments of the inventive compounds of formula I, or theirpharmaceutically acceptable prodrugs, salts, or solvates.

The following specific examples are intended to be illustrative of theinvention and should not be construed as limiting the scope of theinvention as defined by the appended claims. These examples includepreferred embodiments of the inventive compounds.

EXAMPLES Example 1 Preparation of Intermediate Compounds of FormulaVIII-a

Example 1 (a) 4-Phenoxybenzenesulfonyl chloride {VIII-a: Z=H}

To a stirred solution of 42.5 g (0.25 mol) of phenyl ether in 200 mL ofdichloromethane at −20° C. under argon was slowly added 23.3 g (0.20mol) of chlorosulfonic acid. After the addition was complete, thereaction was allowed to slowly warm to room temperature. After 16 h, 150mL of isooctane was added, and the solution was concentrated to an oilyresidue. Redissolution in 200 mL of 1:3 dichloromethane/isooctane andreconcentration with cooling to about 100 mL gave a solid. Thesupernatant was decanted, and the solid triturated with additionalisooctane and then dried in vacuo to give 55.2 g of crude4-phenoxybenzene sulfonic acid. The crude acid was dissolved in 200 mLof dichloromethane, and 22 mL (32 g, 0.25 mol) of oxalyl chloride wasadded, followed by 2.5 mL of N,N-dimethylformamide. After 2 days, thereaction solution was poured into 200 mL of ice water, and extractedwith 400 mL of hexane. The organic layer was washed with 100 mL of waterand 100 mL of brine, dried over magnesium sulfate, and concentrated.Recrystallization of the residue from dichloromethane/isooctane gave38.5 g of 4-phenoxybenzenesulfonyl chloride as a white solid: mp 41.5°C.; ¹H-NMR (CDCl₃) δ 7.10 (apparent T, 4 H, J=7 Hz), 7.28 (t, 1H, J=7Hz), 7.46 (t, 2H, J=8 Hz), 7.98 (d, 2H, J=8.8 Hz).

Example 1 (b) 4-(4-Methylphenoxy)benzenesulfonyl chloride {VIII-a:Z=CH₃}

To a solution of 1.84 g (10.0 mmol) of 4-methyldiphenyl ether (J. Chem.Soc., Perkin Trans. 1; 1992, 407-408, which article is entirelyincorporated herein by reference) with 2 mL of dichloromethane in anice-bath was added a solution of chlorosulfonic acid (0.73 mL, 11.0mmol) in 2 mL of dichloromethane dropwise. The resulting mixture wasstirred at 0° C. to room temperature for 2 hr, and then oxalyl chloride(11.14 mL, 13.0 mmol) was added dropwise, followed by 0.15 mL of DMF.The resulting mixture was heated to 40° C. for 1 hr and then allowed tocool to room temperature over a 2 hr period. The reaction mixture waspoured into ice-pH 7 phosphate buffer (50 mL), then extracted with ethylacetate:Hexane (4:3) (3×150 mL). The combined organic layers were washedwith brine (75 mL). The aqueous layer was extracted with ethylacetate/Hexane(4:3) (150 mL). The organic layer was dried over Na₂SO₄,then evaporated by vacuum to give crude product as white solid. Thissolid was triturated with hexane and collected by filtration, then driedunder high vacuum to give 1.555 g (57%) of4-(4-methylphenoxy)benzenesulfonyl chloride as white solid: mp 295-300°C. ¹H-NMR (dMSO-d6) δ 2.34 (s, 3H), 6.91-6.99 (dd, J=7.7,8.4 Hz, 4H),7.24-7.27 (d, J=8.4 Hz, 2H), 7.61-7.63 (d, J=8.1 Hz, 2H).

Anal. calc. for C₁₃H₁₁O₃SCl: C, 55.22; H, 3.92; S, 11.34; Cl, 12.71.Found: C, 55.06; H, 3.95; S, 11.28; Cl, 12.71.

The following compounds were prepared in a similar fashion:

Example 1 (c) 4-(4-Bromophenoxy)benzenesulfonyl chloride {VIII-a: Z=Br}

From 4-bromobiphenyl ether (supplier: Aldrich): mp 81° C.

Example 1 (d) 4-(4-Chlorophenoxy)benzenesulfonyl chloride {VIII-a: Z=Cl}

From 4-chlorobiphenyl ether (supplier: Transworld): mp 61° C.

Example 1 (e) 4-(4-Fluorophenoxy)benzenesulfonyl chloride {VIII-a: Z=F}

From 4-fluorobiphenyl ether (supplier: Riedel-de Haen): mp 76° C.

Example 1 (f) 4-(4-Iodophenoxy)benzenesulfonyl chloride {VIII-a: Z=I}

From 4-iodobiphenyl ether (supplier: Transworld): mp 85-88° C.

Example 1 (g) 4-(4-Cyanophenoxy)benzenesulfonyl chloride {VIII-a: Z=CN}

From 4-cyanobiphenyl ether (supplier: Transworld): mp 98-102° C.

Example 1 (h) 4-(4-Trifluoromethyphenoxy)benzenesulfonyl chloride{VIII-a: Z=CF₃}

From 4-trifluoromethylbiphenyl ether (J. Chem. Soc., Perkin Trans. 11988, 3229-3232, which article is entirely incorporated herein byreference) mp 265-270° C.; ¹H-NMR (CDCl₃) δ 7.04 (d, J=8.4 Hz, 2H), 7.14(d, J=8.7 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H).

Anal. calc. for C₁₃H₈O₃S₁F₃Cl (336.71): C, 46.34; H, 2.39; S, 9.52.Found: C, 46.34; H, 2.49; S, 9.37.

Example 1 (i) 4-(Pyrid-2-yl)oxybenzenesulfonyl chloride

From 2-phenoxypyridine (supplier: ICN): ¹H-NMR (CDCl₃) δ 8.25 (m, 1H),8.05 (d, 2H, J=9 Hz), 7.81 (t, 1H, J=8 Hz), 7.34 (d, 2H, J=9 Hz), 7.15(dd, 1H, J=7 & 5 Hz), 7.06 (d, 1H, J=8 Hz).

Example 2 Preparation of Intermediate 4-(Pyridin-4-yl)oxybenzenesulfonylChloride Hydrochloride

To a suspension of 4-(pyridin-4-yl)oxybenzenesulfonic acid (1.3 kg) inacetonitrile (8 L), was added N,N-dimethylformamide (12.35 mL), and theviscous reaction mixture was heated to 75° C. Thionyl chloride (756 mL)was added to the reaction mixture over 30 minutes. The reaction mixtureslowly became less viscous and became homogeneous after 45 minutes,which indicated the reaction was complete. A portion of the solvent (4L) was evaporated under vacuum and tert-butyl methyl ether (4 L) wasadded. The resulting slurry was filtered under inert atmosphere. Thefilter cake was rinsed with tert-butyl methyl ether (2 L), and the soliddried under vacuum to yield 4-(pyridin-4-yl)oxybenzenesulfonyl chloridehydrochloride (1.35 kg) as a hygroscopic, off-white solid of pearlescentflakes: mp 182° C.; ¹H NMR (CDCl₃): δ 8.87 (d, J=7 Hz, 2H), 8.24 (d,J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.43 (d, J=7 Hz, 2H).

The starting material was prepared as follows:

To a vigorously stirred solution of 4-phenoxypyridine (1 kg) in dry1,2-dichloroethane (3 L) at −10° C. under a stream of argon,chlorosulfonic acid (974 mL) was added slowly. The addition rate of thechlorosulfonic acid was adjusted to keep the reaction temperature below0° C. After half of the chlorosulfonic acid was added, the exothermstopped. The cooling bath was removed, and the addition ofchlorosulfonic acid continued over 3 hours while the reaction solutionwarmed to room temperature. While continually purging with inert gas,the vigorously stirred reaction mixture was heated to 45° C. By thinlayer chromatography analysis, no more starting material remained after20 hours.

The reaction mixture was cooled to room temperature and slowly pouredinto ice cold water (5 L) while stirring. Potassium phosphate tribasic(212 g) was added as a solid to the mixture, and this was stirred for 10minutes followed by addition of sodium hydroxide (2M) to pH 2. Afterstirring for 1 hour, the pH was changed to 7 by the addition of sodiumhydroxide (2M). Agitation was continued for 5 minutes, and then theorganic layer was drained off and discarded. The mixture was extracted asecond time with dichloromethane (2L), the mixture agitated for 5minutes, and the organic layer drained off and discarded. The remainingaqueous mixture was extracted by addition of dichloromethane (6 L),tetrabutylammonium bromide (940 g), and sodium hydroxide (2M) to pH 7.The mixture was agitated for 5 minutes and the organic layer (bottom)drained into a flask. The extraction procedure was repeated twice. Thecombined organic was dried over magnesium sulfate, filtered, and thesolution was concentrated under vacuum to an oil. The residual oil wasdiluted with 20% ethanol in ethyl acetate (8 L, dry), and hydrogenchloride gas added to a pH of 1. The solid was filtered off and thefilter cake rinsed with 20% ethanol in ethyl acetate (2 L). The solidwas dried under vacuum at 45° C. for 15 hours to yield4-[(pyrid-4-yl)oxy]benzenesulfonic acid(1.3 kg) as a white powderysolid.

mp dec. >275 ° C.; ¹H NMR (300 MHZ, DMSO-d₆): δ 8.86 (dd, J=1.5, 7.4 Hz,2H), 7.84 (dd, J=1.5, 7 Hz, 2H)7.54 (dd, J=1.5, 7.4 Hz, 2H), 7.35 (dd,J=1.5, 7 Hz, 2H). ‘Anal. calc. for C₁₁H₉NO₄S: C, 52.58; H, 3.61; N,5.57; S, 12.76. Found: C, 52.50; H, 3.69; N, 5.51; S, 12.67.

Example 3 Preparation of Compounds of Formula I

Example 3(a).2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-3-methylbutanamide

Dry hydrogen chloride was bubbled through a −20° C. solution of2(R)-N-(tert-butoxy)-2-[4-(4-bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-3-methylbutanamide(750 mg, 1.27 mol) in 20 mL of dichloromethane for 10 min, and thereaction was sealed and stirred at room temperature overnight. Thereaction was vented, nitrogen was bubbled through the solution for 20min, and the solution was concentrated to give, after trituration withether, 689 mg (79%) of2(R)-2-[4-(4-bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-3-methylbutanamideas a white solid: mp 142.3-143.7° C.; El MS m/e 533 (M⁺)

Anal. Calcd. for C₂₃H₂₄BrN₃O₅S•HCl: C, 48.39; H, 4.41; N, 7.36. Found:C, 48.03; H,4.46; N,7.51.

The starting material was prepared as follows:

(i) Preparation of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valinet-butyl ester

To a 0° C. suspension of 4-(4-bromophenoxy)benzene sulfonyl chloride(1.10 g, 3.16 mmol) in 20 mL of dichloromethane was added a solution ofdiisoproylethylamine (1.10 mL, 6.3 mmol) and D-valine tert-butyl ester(660 mg, 3.8 mol) in 11 mL of dichloromethane. The ice bath was removed,and the reaction was stirred for 3 h, diluted with 30 mLdichloromethane, and 30 ml of 1 M HCl was added. The layers wereseparated, and the aqueous layer was washed with 30 mL ofdichloromethane. The combined dichloromethane fractions were washed withbrine, dried over MgSO₄, and concentrated. The residue waschromatographed on silica, eluting with 25% ethyl acetate in hexane, togive 980 mg (64%) of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valinet-butyl ester as a white foam.

(ii) Preparation ofN-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valinet-butyl ester

To a solution of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valine t-butylester (980 mg, 2.0 mol) in 5 mL of DMF was added potassium carbonate(1.53 g, 11.1 mol), 3-picolyl chloride hydrochloride (414 mg, 2.53 mol),and Kl (67 mg, 0.4 mol). The reaction was stirred at room temperatureovernight. An additional 220 mg of picolyl chloride hydrochloride wasadded, and the reaction was stirred for 3 h. Water (25 mL) and ethylacetate (50 mL) were added, and the layers were separated. The ethylacetate fraction was washed with brine, dried over MgSO₄, andconcentrated. The residue was purified by chromatography on silica,eluting with 35% ethyl acetate in hexane, to give 1.07g (92%) ofN-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valinet-butyl ester as a tan foam.

(iii) Preparation of2(R)-N-(tert-butoxy)-2-[4-(4-bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-3-methylbutanamide

Dry hydrogen chloride was bubbled through a −20° C. solution ofN-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valinet-butyl ester (920 mg, 1.6 mol) in 20 mL of dichloromethane for 10 min,and the reaction was sealed and stirred at room temperature overnight.The reaction was vented, nitrogen was bubbled through the solution for20 min, and the solution was concentrated to giveN-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valinehydrochloride that was used without further purification in the nextstep. The above acid was dissolved in 8 mL of dichloromethane, treatedwith O-t-butyl hydroxylamine hydrochloride (600 mg, 4.8 mol),N-methylmorpholine (0.92 mL, 8.3 mol), and EDC (613 mg, 3.2 mol), andstirred at room temperature overnight. The reaction was partitionedbetween water and dichloromethane, and the organic phase was washed withbrine, dried over MgSO₄, and concentrated. The residue was purified bychromatography on silica, eluting with 5% methanol in dichloromethane,to give 750 mg (79%) of2(R)-N-(tert-butoxy)-2-[4-(4-bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-3-methylbutanamideas a clear oil.

The following compound was prepared in a similar manner:

Example 3(b)2(R)-N-hydroxy-2-[(4-phenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-3-methylbutanamide

El MS m/e 473 (M⁺)

Anal. Calcd. for C₂₃H₂₅N₃O, S•HCl•0.5 H₂O: C, 55.14; H, 5.03; N, 78.39.Found: C, 55.40; H, 5.42; N, 8.49.

Example 42(R)-2-[(diethylphosphonomethyl)(4-phenoxybenzenesulfonyl)amino]-N-hydroxyacetamide

A solution of benzyl2-[(diethylphosphonomethyl)(4-phenoxy-benzenesulfonyl)amino]acetate (1.0g, 1.8 mmol) in 20 ml of ethyl acetate and 250 mg of 10% Pd on carbonwas stirred under 1 atm of hydrogen for 3 h. The reaction was filteredthrough celite and concentrated. The residue,2(R)-2-[(diethylphosphonomethyl)(4-phenoxybenzenesulfonyl)amino]-aceticacid, was dissolved in 20 mL of dichloromethane and treated withO-benzylhydroxylamine (0.25 g, 2.0 mmol), EDC (0.80 g, 4.1 mol), and4-dimethylaminopyridine (50 mg, 0.4 mol). After 3 h, the reaction waspartitioned between 50 mL of water and 100 mL ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated. The residue wasdissolved in 20 mL of 5% ethanol in ethyl acetate, and 250 mg of 10% Pdon carbon was added, and the reaction was stirred under 1 atm ofhydrogen. The reaction was stopped at approximately 70% conversion whenTLC analysis indicated that over-reduction of the product to the primaryamide was beginning to occur. The mixture was filtered through celiteand concentrated, and the residue was purified by PTLC (10% methanol indichloromethane) to provide 360 mg (42%) of2(R)-2-[(diethylphosphonomethyl)(4-phenoxybenzenesulfonyl)amino]-N-hydroxyacetamideas a white foam: FAB MS m/e 473 (M+H)⁺

The starting material was prepared as follows:

(i) Preparation ofDiethyl[(4-phenoxy)benzenesulfonyl]aminomethylphosphonate

A solution of diethyl (N-benzyl)aminomethylphosphonate (2.5 g, 9.7 mmol)in 30 ml of EtOH and 0.5 g of Pd(OH)₂ was stirred under an atmosphere ofhydrogen (1 atm) overnight. The reaction was filtered through celite andconcentrated to give diethyl aminomethylphosphonate (600 mg, 3.6 mol).The crude phosphonate was dissolved in 30 ml of dichloromethane, cooledto 0° C., and treated with 4-phenoxybenzenesulfonyl chloride (800 mg, 3mol) and triethylamine (1 ml, 7.2 mol). The ice bath was removed, thereaction was stirred for 4 h, and 20 mL of 5% HCl was added. The aqueouslayer was extracted with 30 mL of dichloromethane, and the combineddichloromethane fractions were washed with brine, dried over magnesiumsulfate, and concentrated to givediethyl[(4-phenoxy)benzenesulfonyl]aminomethylphosphonate (1.26 g, 88%)as a clear oil.

(ii) Preparation of Benzyl2(R)-2-[(diethylphosphonomethyl)(4-phenoxybenzenesulfonyl)amino]acetate

A 0° C. solution ofdiethyl[(4-phenoxy)benzenesulfonyl]aminomethylphosphonate (1.26 g, 3.2mol) in 20 mL of DMF was treated with NaH (130 mg, 3.3 mol) and stirredfor 30 min. Benzyl 2-bromoacetate (6.76 g, 3.3 mol) was added, and thereaction was stirred for 2 h at 0° C. and allowed to warm to roomtemperature. After 16 h, the reaction was partitioned between 100 mL ofethyl acetate and 50 mL of 5% aq. HCl. The organic layer was washed withbrine, dried over magnesium sulfate, and concentrated. The residue waschromatographed on silica, eluting with 40% to 70% ethyl acetate inhexane, to give benzyl2(R)-2-[(diethylphosphonomethyl)(4-phenoxybenzenesulfonyl)amino]acetate(1.0 g, 56%) as a clear oil.

Example 4(a)2(R)-2-[(diethylphosphonomethyl)(4-phenoxybenzenesulfonyl)-amino]-aceticacid

This compound can be prepared as described in Example 4 above.

Example 52(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxypiperidine-2-carboxamide

To a solution of2(R)-1-[4-(4-bromophenoxy)benzenesulfonyl]piperidine-2-carboxylic acid(100 mg) in dimethylformamide (1 ml, dry), was added N-methylmorpholine(0.05 ml), followed by the BOP reagent (0.156 g), and this mixture wasstirred for 15 minutes at room temperature. Hydroxylamine hydrochloridewas added to the reaction as a solid followed by additionalN-methylmorpholine (0.076 ml). The reaction was stirred for three hours,and TLC showed no trace of starting material. The reaction mixture waspoured into sodium bicarbonate solution (1M, 10 ml), extracted withethyl acetate/hexanes (5:1), (3×50 ml), and the combined organicfractions were washed with brine, then water, and dried over sodiumsulfate. The solvent was removed, the residue was chromatographed with4% ethanol in dichloromethane, the solvent was removed from the combinedproduct fractions, and the residue was solvated in refluxing ethylacetate. Isooctane was added to this mixture until milky, and thesolvent was removed under vacuum to give2(R)1-[4-(4-bromophenoxy)benzenesulfonyl]-piperidine-2-carboxylic acidhydroxyamide (0.065 g) as an off-white foam: mp 88-92° C.; ¹H NMR(MeOD-d₄): δ 7.76 (dd, J=2 Hz, 9 Hz, 2H), 7.52 (dd, J=2 Hz, 9 Hz, 2H),7.05 (dd, J=2 Hz, 9 Hz, 2H), 7.01 (dd, J=2 Hz, 9 Hz, 2H), 4.39(br s,1H), 3.73 (d, J=10 Hz, 1H), 3.45-3.33 (m, 1H), 1.94-1.84 (m, 1H),1.6-1.45 (m, 4H), 1.35-1.22 (m, 1H).

Anal. calc. for C₁₈H₁₉BrN₂O₅S: C, 47.48; H, 4.21; N, 6.15; S, 7.04.Found C, 47.66; H, 4.36; N, 6.15; S, 6.96.

The starting material was prepared as follows:

(i) Preparation of2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]piperidine-2-carboxylic acid

To a stirred suspension of the 2(R)-pipecolic acid (4.0 g) indichloromethane (200 ml) at 0° C. was added trimethylsilyl chloride (4.3ml). After complete addition of the trimethylsilyl chloride, thereaction became homogeneous, and the reaction was warmed to roomtemperature. Triethylamine (10.58 ml) was added, and the reaction wasstirred for 15 minutes followed by the addition of the4-(4-bromophenoxy)-benzenesulfonyl chloride (10.76 g) as a solution indichloromethane (100 ml). After two hours, the reaction mixture waspoured into pH 4 citrate buffer (0.5 M), and this was extracted withdichloromethane (3×250 ml). The combined organic layers were dried oversodium sulfate and concentrated. The residue was chromatographed onsilica, eluting with 8% ethanol in dichloromethane. Recrystallizationfrom ethyl acetate/isooctane provided, in three crops, 13.51 g of2(R)1-[4-(4-bromophenoxy)benzenesulfonyl]piperidine-2-carboxylic acid(13.51 g) as an off-white solid: mp 185° C.; ¹H NMR (CDCl₃) δ 7.75 (dd,J=2 Hz, 9 Hz, 2H), 7.5 (dd, J=2 Hz, 9 Hz, 2H), 7.0 (dd, J=2 Hz, 9 Hz,2H), 6.96 (dd, J=2 Hz, 9 Hz, 2H), 4.78 (d, J=5 Hz, 1H), 3.72 (d, J=3 Hz,1H), 3.19 (ddd, J=3 Hz, 12.5 Hz, 13 Hz, 1H), 2.18 (dd, J=2 Hz, 13 Hz,1H), 1.83-1.60 (m, 3H), 1.55-1.22 (m, 2H).

Anal. calc. for C₁₈H₁₈BrNO₅S: C, 49.10; H, 4.12; N, 3.18; Found: C,48.97; H, 4.12; N, 3.19.

Example 5(a)2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxypiperidine-2-carboxylicacid

This compound can be prepared as described in Example 5 above.

Example 62(R)-1-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide

To a solution of2(R)-N-(t-butyldiphenylsilyl)oxy-1-[4-(biphenyl-4-yl)oxybenzenesulfonyl]piperidine-2-carboxamide(0.21 g) in ethyl acetate/methanol (1:1, 50 ml), was added Amberlite(F⁻) resin in three portions (3×0.025 g), over one hour. After fourhours, the reaction was complete by TLC, the resin was removed byfiltration, and the filtrate was concentrated. The residual oil waschromatographed with 7% ethanol, and 5% ethyl acetate in dichloromethaneto give, after concentration from dichloromethane/t-butyl methyl ether,2(R)-1-[4-(biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide(0.115 g) as an off-white foam:

¹H NMR (CDCl₃): δ 9.25 (s, 1H), 7.8 (d, J=9 Hz, 2H), 7.64 (d, J=8 Hz,2H), 7.58 (d, J=7 Hz, 2H), 7.5-7.35 (m, 4H), 7.15 (d, J=11 Hz, 2H), 7.11(d, J=11 Hz, 2H), 4.58 (d, J=4 Hz, 1H), 3.9-3.82 (d, J=14 Hz,1H), 3.11(dd, J=13, 13 Hz, 1H), 2.27 (d, J=13 Hz, 1H), 1.85-1.2 (m, 5H).

Anal. calc. for C₂₄H₂₄N₂O₅S•0.65 MTBE: C, 64.20; H,6.29; N, 5.50; S,6.29. Found: C, 64.51; H, 6.28; N, 5.76; S, 6.57.

The starting material was prepared as follows:

(i) Preparation of2(R)1-[4-(Biphenyl4-yloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid

To a suspension of2(R)1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid(0.44 g) in benzene (4 ml), a solution of sodium carbonate (2M, 2 ml)was added. Argon gas was bubbled through the stirred reaction mixture,and tetrakistriphenylphosphine palladium(0) (0.116 g) was added,followed by phenylboronic acid (0.36 g) as a solution in ethanol (4 ml).The reaction mixture was heated to reflux for 24 hours, cooled andpoured into pH=4 buffer (1M, 50 ml), and extracted with dichloromethane(3×100 ml), and the combined organic extracts were washed with water,dried over sodium sulfate, and the solvent removed. The residue waschromatographed with 5% methanol in dichloromethane with 0.1% aceticacid. The product fractions were stripped down, ethyl acetate was added,followed by isooctane, and the solution was stripped down to give2(R)1-[4-(Biphenyl-4-yloxy)-benzenesulfonyl]-piperidine-2-carboxylicacid as a beige foam: mp 77-81° C.; ¹H NMR (CDCl₃): δ 7.76 (dd, J=2 Hz,9 Hz, 2H), 7.65-7.57 (m, 4H), 7.5-7.4 (m, 2H), 7.38-7.3 (m, 1H), 7.12(dd, J=2 Hz, 9.5 Hz, 2H), 7.06 (dd, J=2 Hz, 9 Hz, 2H), 4.8 (d, J=5 Hz,1H), 3.74 (d, J=12 Hz, 1H), 3.21( dd, J=11 Hz, J =12 Hz, 1H), 2.2 (d,J=12 Hz, 1H), 1.8-1.6 (m, 3H), 1.55-1.25 (m, 2H).

Anal. calc. for C₂₄H₂₃NO₅S: C, 65.88; H, 5.30; N, 3.20. Found: C, 65.97;H, 5.53; N, 3.14.

(ii)2(R)-1-[4-(Biphenyl-4-yloxy)-benzenesulfonyl]-N-(t-buyldiphenylsilyl)oxy-piperidine-2-carboxamide

To a solution of2(R)1-[4-(Biphenyl4-yloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid(0.219 g) in dichloromethane (10 ml), dimethylformamide (0.008 ml) wasadded, and the solution was cooled to −5° C. Oxalyl chloride (0.066 ml)was added, and the reaction was stirred for 30 minutes, then cooled to−78° C., and a solution of the diphenyl-t-butyl silyl chloride (0.217 g)and pyridine (0.121 ml) in dichloromethane (4 ml) was added. Thereaction was monitored by TLC and after two hours was complete. Thereaction was poured into ethyl acetate/hexanes (3:1, 100 ml); washedwith ammonium chloride (2M, 20 ml), sodium bicarbonate (2M, 20 ml), andbrine (20 ml); and dried over sodium sulfate. The solvent was removed,and the residue was chromatographed using ethylacetate/dichloromethane/hexanes (1:5:4), the product containingfractions were collected and the solvent removed. The product oil wasdiluted with dichloromethane, isooctane was added, and the mixture wasstripped down to give the product2(R)-N-(t-butyldiphenylsilyl)oxy-1-[4-(Biphenyl-4-yloxy)-benzenesulfonyl]-piperidine-2-carboxamide(0.261 g) as a beige foam: mp 80-84° C.; ¹H NMR (CDCl₃): δ 7.8-7.72 (m,4H), 7.7-7.55 (m, 5H), 7.48-7.32 (m, 10H), 7.12 (d, J=8.5 Hz, 2H), 7.02(d, J=8.5 Hz, 2H), 4.26 (m, 1H), 3.54 (m, 1H), 3.34 (m, 1H), 2.1 (m,1H), 1.6 (m, 1H), 1.4 (m, 1H), 1.17(s, 9H), 1.15-1.0 (m, 4H).

Example 6(a)2(R)-1[4-(Biphenyl-4-yl)oxybenzenesulfonyll-N-hydroxy-piperidine-2-carboxylicacid

This compound can be prepared as described in Example 6 above.

Example 72(R)-1-(4-Phenoxy-benzenesulfonyl)-N-hydroxy-piperidine-2-carboxamide

To a solution of2(R)-N-(t-butyldiphenylsilyl)oxy-1-(4-Phenoxy-benzenesulfonyl)-piperidine-2-carboxamide(0.305 g) in ethyl acetate/methanol (15:85, 50 ml), was added fluorine(F−) resin in three portions (3×0.05 g), over one hour. After 3.5 hours,the reaction was complete by TLC, and the resin was filtered-off, rinsedwith methanol, and the solvent removed. The residual oil waschromatographed with 7% methanol and 5% ethyl acetate indichloromethane. The product fractions were combined, anddichloromethane was added, followed by isooctane, and the mixture wasstripped-down to give the product2(R)-1-(4-Phenoxy-benzenesulfonyl)-N-hydroxy-piperidine-2-carboxamide(0.091 g), as a beige foam: ¹H NMR (CDCl₃): δ 9.32 (s, 1H), 7.78 (d,J=9Hz, 2H), 7.42 (dd, J=8, 8Hz, 2H), 7.22-7.19 (m, 1H), 7.08 (d, J=8.5Hz, 2H), 7.05 (d, J=9 Hz, 2H), 4.58 (d, J=4 Hz, 1H), 3.85 (d, J=14 Hz,1H), 3.18-3.04 (m, 1H), 2.26 (d, J=13 Hz, 1H), 1.7-1.0 (m, 5H).

Anal. calc. for C₁₈H₂₀N₂O₅S•0.26 methanol+0.13 isooctane: C, 58.01; H,5.90; N, 7.01; S, 8.02. Found: C, 58.07; H, 5.78; N, 7.05; S, 7.99.

The starting material was prepared as follows:

(i) Preparation of2(R)-1-(4-Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acid

To a solution of2(R)1-[4-(4-Bromophenoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid(0.22 g) in ethyl acetate (50 ml), was added 10% palladium on carboncatalyst (20% by weight, 0.044 g). The mixture was evacuated, chargedwith hydrogen gas, and stirred for 24 hours under balloon pressure ofhydrogen. The catalyst was filtered-off and the solvent removed. Theresidue was chromatographed using 5% ethanol in dichloromethane with0.1% acetic acid. The solvent was removed from the combined productfractions, isooctane was added, and the solution was stripped-down toyield 2(R)-1-(4-phenoxybenzenesulfonyl)-piperidine-2-carboxylic acid(0.145 g) as a yellow foam: ¹H NMR (CDCl₃):δ 7.74 (d, J=9 Hz, 2H), 7.41(dd, J=8, 8 Hz, 2H), 7.21 (dd, J=7.5, 7.5 Hz, 1H), 7.06 (d, J=8 Hz, 2H),7.0 (d, J=9 Hz, 2H), 4.78 (d, J=4 Hz, 1H), 3.73 (d, J=12.5 Hz, 1H), 3.19(ddd, J=2.5, 10.5, 12.5 Hz, 1H), 2.18 (d, J=14 Hz, 1H), 1.8-1.2 (m, 5H).

(ii) Preparation of2(R)-N-(t-Butyldiphenylsilyl)oxy-1-(4-phenoxy-benzenesulfonyl)-piperidine-2-carboxamide

To a solution of the yield2(R)-1-(4-phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acid (0.21 g)in dichloromethane (10 ml), dimethylformamide (0.008 ml) was added andthe solution cooled to −5° C. Oxalyl chloride (0.075 ml) was added, andthe reaction was stirred for 30 minutes, then cooled to −78° C., and asolution of diphenyl-t-butyl silyl chloride (0.251 g) and pyridine(0.141 ml) in dichloromethane (4 ml) was added. The reaction wasmonitored by TLC and after two hours was complete. The reaction waspoured into ethyl acetate/hexanes (3:1, 100 ml); washed with ammoniumchloride (2M, 20 ml), sodium bicarbonate (2M, 20 ml), and brine (20 ml);and dried over sodium sulfate. The solvent was removed from the productoil, which was diluted with dichloromethane, isooctane was added, andthe mixture was stripped down to give the product2(R)-N-(t-butyldiphenylsilyl)oxy-1-(4-phenoxy-benzenesulfonyl)-piperidine-2-carboxamide(0.31 g) as an oil, which was used without further purification.

The results obtained during biological testing of some preferredembodiments of the inventive compounds are described below.

BIOLOGICAL DATA

Isolation of MMP's for Assays

The catalytic domain of human collagenase-1 was expressed as a fusionprotein with ubiquitin in E. coli (see Gehring, E. R., J. Biol. Chem.,1995, 270, 22507, which article is entirely incorporated herein byreference). After purification of the fusion protein, the fibroblastcollagenase-1 catalytic domain (HFC) was released either by treatmentwith purified, active stromelysin-1 (1:50 w/w ratio), which generatednearly 100% N-terminal Phe1, or by autoprocessing the concentratedcollagenase-1 fusion and then incubating at 37° C. for 1 hour. Finalpurification was completed using zinc chelate chromatography.

The propeptide and catalytic domain of human collagenase-3 (Coll3) wasexpressed in E. coli as an N-terminal fusion protein with ubiquitin.After purification of the fusion from inclusion bodies, the catalyticdomain was liberated by treatment with 2mM APMA at room temperatureovernight. Final purification was completed using copper chelatechromatography.

The catalytic domain of human stromelysin (Sln) was obtained byexpression and purification of a C-terminally truncated prostromelysin-1from E. coli host BL21 (see Marcy et al. Biochem., 1991, 30, 6476, whicharticle is entirely incorporated herein by reference). The subsequentactivation of the mature form (Sln) was completed with 2mM APMA for 1hour at 37° C., followed by separation using a sizing column.

Human matrilysin (Matr) was expressed in E. coli as a fusion proteinwith ubiquitin. After purification of the matrilysin/ubiquitin fusionfrom inclusion bodies, the catalytic domain was liberated by treatmentwith 2mM APMA at 37 ° C. for 2 hours. Final purification was completeusing copper chelate chromatography.

The catalytic and fibronectin-like portion of human progelatinase A(GelA) was expressed as a fusion protein with ubiquitin in E. Coli.Assays were carried out on autocatalytically activated material.

Compounds of Formula I exhibited the ability to inhibit MMPs when testedin the following assay.

In Vitro Assay Procedure

Assays were performed in assay buffer (50 mM Tricine pH 7.5, 200 mMsodium chloride, 10 mM calcium chloride, 0.5 mM zinc acetate containing2% dimethyl sulfoxide (DMSO)), once the substrate and inhibitor werediluted into it. Stock solutions of inhibitors were prepared in 100 %DMSO. Stock solutions of the substrate were prepared in 100 % DMSO at aconcentration of 6 mM.

The assay method was based on the hydrolysis ofMCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂ (American Peptide Co.) at 37° C.(see Knight, C. G. et al., FEBS, 1992, 296, 263-266, which article isentirely incorporated herein by reference). The fluorescence changeswere monitored with a Perkin-Elmer LS-50B fluorimeter using anexcitation wavelength of 328 nm and an emission wavelength of 393 nm.The substrate concentration used in the assays was 10 μM. The inhibitorwas diluted into the assays from a solution in 100 % DMSO, and controlssubstituted an equal volume of DMSO so that the final DMSO concentrationfrom inhibitor and substrate dilution in all assays was 2%. Theconcentration of enzyme in the assay ranged from 60 pM for gelatinase Ato 1.5 nM for stromelysin and is a function of the enzymes respectivek_(cat)/K_(m) for the MCA peptide substrate. Proper determination ofsteady-state rates of substrate cleavage required assay lengths of 60minutes to allow for complete equilibration of the enzyme-inhibitorcomplex.

The K_(m) for the MCA peptide substrate with the matrixmetalloproteinases is quite high and exceeds its solubility under assayconditions. Consequently, the apparent K_(i) (K_(i, app)) was determinedto describe the strength of inhibition. However, in this case, K_(i,app)would be essentially equal to K_(i) since [S]<<K_(m). For thedetermination of K_(i,app), the concentration of the inhibitor wasvaried at a constant and low concentration of substrate, and thesteady-state rates of fluorescence change were determined. In mostcases, absorptive quench due to the presence of ligand was not observed.For slow-binding inhibitors, onset of inhibition curves were collectedfor at least 45 minutes so that equilibrium was established.Steady-state rates of fluorescence change were obtained by fitting acurve to an equation for a single exponential decay containing a linearphase. The fitted value of the linear phase was taken as thesteady-state rate. The steady-state rates were fitted to the Michaelisequation describing competitive inhibition by non-linear methods. Dataresulting from tight-binding inhibition was analyzed, and K_(i,app)determined by fitting the data to the tight-binding equation of Morrison(Biochem. Biophys. Acta, vol. 185, pp. 269-286 (1969), which article isentirely incorporated herein by reference) by non-linear methods.

The results of the above-described tests are presented below in Table 1.All Ki values are in nM units.

TABLE 1 Ki values (nM) Example # Strom HFC Matr Gel A Coll-3 3(a) 0.357.6 0.02 3(b) 1.2 6.0 0.05 4 0.23 27 0.09 4(a) 27,000 740 5 0.04 15 440.018 0.014 5(a) 16,000 481,000 540,000 192 448 6 0.06 8.8 6.7 0.0140.008 6(a) 2190 125,000 72,000 64 212 7 0.07 6.6 55 0.007 0.007

In describing the invention, applicant has set forth certain theories inan effort to disclose how or why the invention works in the manner inwhich it works. These theories are set forth for informational purposesonly. Applicant is not to be bound by any specific chemical or physicalmechanisms or theories of operation.

While the invention has been described in terms of various preferredembodiments and specific examples, those skilled in the art willrecognize that various changes and modifications can be made withoutdeparting from the spirit and scope of the invention, as defined in theappended claims.

What is claimed is:
 1. A compound of formula l:

wherein: Ar is an aryl group or a heteroaryl group; X is —NH—OH or —OH:R₁ is H, —CH(R₃)(R₄), —C(O)R₃, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, or a heteroaryl group, wherein R₃ is H or anysuitable substituent and R₄ is H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; R₂ isCH₂-R₅, wherein R₅ is H or any suitable substituent, or wherein R. andR₄ are optionally substituted carbon atoms singly- or double-bonded toone another; or a pharmaceutically acceptable prodrug, salt or solvatethereof.
 2. A compound according to claim 1, wherein R₃ is hydrogen, analkyl group, a cycloalkyl group, a heterocycloalkyl group, an arylgroup, a heteroaryl group, —OR₁₀, —SR₁₀, C≡C-R₁₀, —C(O)OR₁₀, C(O)NHR₁₀,wherein R₁₀ is hydrogen, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or apharmaceutically acceptable prodrug, salt, or solvate thereof.
 3. Acompound according to claim 1, wherein said compound has the formula II:

wherein R₁, R₂, and X are as defined in claim 1 and Z is a halogengroup, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, anO-alkyl group, an S-alkyl group, an aryl group, or a heteroaryl group;or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
 4. Acompound according to claim 1, wherein Ar is a heteroaryl groupcontaining six ring atoms; or a pharmaceutically acceptable prodrug,salt, or solvate thereof.
 5. A compound according to claim 4, wherein Aris pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl; or apharmaceutically acceptable prodrug, salt, or solvate thereof.
 6. Acompound according to claim 1, wherein R₅ is H and R₄ is an alkyl group;or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
 7. Acompound according to claim 1, wherein R₅ is a heteroaryl group; or apharmaceutically acceptable prodrug, salt, or solvate thereof.
 8. Acompound according to claim 1, wherein R₅ is —CHR₆R₇, wherein R₆ is H orany suitable substituent and R₇ is

wherein R₈ is any suitable substituent; or a pharmaceutically acceptableprodrug, salt, or solvate thereof.
 9. A compound according to claim 1,wherein R₄ is an alkyl group and R₃ is an alkyl group, an O-alkyl group,or an S-alkyl group; or a pharmaceutically acceptable prodrug, salt, orsolvate thereof.
 10. A compound according to claim 9, wherein R₃ is a—CH₂CH₂-heteroaryl group, an —OCH₂—; heteroaryl group, or an—S—CH₂-heteroaryl group; or a pharmaceutically acceptable prodrug, salt,or solvate thereof.
 11. A compound according to claim 1, wherein R₄ andR₅ together form the group —CH₂CH₂—; or a pharmaceutically acceptableprodrug, salt, or solvate thereof.
 12. A compound according to claim 1,wherein the compound is:2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-Methylphenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-Phenoxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(2-(Dimethylamino)ethyl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxypiperidine-2-carboxamide,2(R),3(S)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R),3(S)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-3-methyl-piperidine-2-carboxamide,2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin4-yl)methyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(imidazol-2-yl)methyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-2-yl)ethyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-4-yl)ethyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(pyrazol-3-yl)ethyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylamino)ethyl]amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-cyclohexylacetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-2-yl)ethyl]amino-N-hydroxy-2-cyclohexylacetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino-N-hydroxy-2-cyclohexylacetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hydroxy-2-(1-acetylpiperidin-4-yl)acetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesuifonyl][(2-(methylcarbamoyl)ethyl]amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N,3-dihydroxybutanamide,2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methoxybutanamide,2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-(2-methoxyethoxy)butanamide,2(R), 3(R),3(2′(S))-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-oxopyrrolidin-2-yl)methoxy]butanamide,2(R),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methoxy]butanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohexylacetamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,2(S)3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl)(methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylpiperidin-4-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[2-(dimethylamino)ethylsulfanyl]butanamide,2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]propanamide,2(S)-2-(4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]propanamide,2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]propanamide,2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N,3-dihydroxybutanamide,2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methoxybutanamide,2(R), 3(R)-2-[4-(4-Fluorophanoxy)bnenenesulfonyl](methyl)amino-N-hydroxy-3-(2-methoxyethoxy)butanamide, 2(R),3(R),3(2′(S))-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-oxopyrrolidin-2-yl)methoxy]butanamide,2(R),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methoxy]butanamide,2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohexylacetamide,2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylpiperidin-4-yl)methylsulfanyl]butanamide,2(S),3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[2-(dimethylamino)ethylsulfanyl]butanamide,2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]propanamide,2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyrid-2-yl)methylsulfanyl]propanamide,2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]propanamide,2(R),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N,3-dihydroxybutanamide,2(R),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methoxybutanamide,2(R),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-(2-methoxyethoxy)butanamide,2(R), 3(R),3(2′(S))-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-oxopyrrolidin-2-yl)methoxy]butanamide,2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohexylacetamide,2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclopentylacetamide,2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclopropylacetamide,2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,2(S),3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-methylisoxazol-3-yl)methylsulfanyl]butanamide,2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-(hydroxymethyl)isoxazol-3-yl)methylsulfanyl]propanamide,2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(phenyl)methylsulfanyl]propanamide,2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(4-fluorophenyl)methylsulfanyl]propanamide,2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-methylimidazol-2-yl)methylsulfanyl]propanamide,2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Methylphenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-Methoxyphenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-Phenoxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-2-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-2-[4-(4-(2-(dimethylamino)ethyl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide,2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-Methylphenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-Phenoxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-(4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,2(R)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(4-(2-(Dimethylamino)ethyl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,2(R),3(S)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide,or 2(R),3(S)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H-azepine-2-carboxamide;or a pharmaceutically acceptable prodrug, salt, or solvate thereof. 13.A pharmaceutical composition comprising: (a) a therapeutically effectiveamount of a compound as defined in claim 1 or a pharmaceuticallyacceptable prodrug, salt, or solvate thereof; and (b) a pharmaceuticallyacceptable carrier, diluent, vehicle, or excipient.
 14. A method oftreating a mammalian disease condition mediated by metalloproteinaseactivity which comprises administering to a mammal in need thereof atherapeutically effective amount of a compound as defined in claim 1 ora pharmaceutically acceptable prodrug, salt, or solvate thereof.
 15. Amethod according to claim 14, wherein the mammalian disease condition istumor growth, invasion, or metastasis.
 16. A method according to claim14, wherein the mammalian disease condition is osteoarthritis,rheumatoid arthritis, osteoporosis, periodontitis, or gingivitis.
 17. Amethod according to claim 14, wherein the mammalian disease condition ischronic dermal wounds, corneal ulceration, or degenerative skindisorders.
 18. A method according to claim 14, wherein the mammaliandisease condition is multiple sclerosis or stroke.
 19. A methodaccording to claim 14, wherein the mammalian disease condition isatherosclerosis or glomerular disease.
 20. A method according to claim14, wherein the mammalian disease condition is characterized by unwantedangiogenesis.
 21. A method according to claim 14, wherein the mammaliandisease condition is diabetic retinopathy, macular degeneration,angiofibromas, or hemangiomas.
 22. A method according to claim 14,wherein the mammalian disease condition is mediated by matrixmetalloproteinase activity.
 23. A method according to claim 14, whereinthe mammalian disease condition is mediated by TNF-α convertaseactivity.
 24. A method of inhibiting the activity of at least onemetalloproteinase which comprises contacting said at least onemetalloproteinase with an effective amount of a compound as defined inclaim 1 or a pharmaceutically acceptable prodrug, salt, or solvatethereof.
 25. A method according to claim 24, wherein said at least onemetalloproteinase is a matrix metalloproteinase.
 26. A method accordingto claim 25, wherein said at least one metalloproteinase is a TNF-αconvertase.